We estimate the penetrance of LQTS for KCNQ1 T155A is 57%. We are unaware of any observations of this variant in individuals. T155A is not present in gnomAD. T155A has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T155A around 57% (5/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.92	0.033	1	0.677	66

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

PubMed ID	Year	Carriers	Unaffected	LQT1	Other Disease
LITERATURE, COHORT, AND GNOMAD:	-	0	0	0
VARIANT FEATURES ALONE:	-	10	5	5	-

Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional K_V7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor	Distance (Angstroms)	Variants Observed in Individuals
155	0
154	4
156	4
152	5
159	6	M159del,
153	6	T153M,
158	7
151	7
139	7
157	8	F157C,
160	9	E160del, E160K, E160V,
149	9
150	9	A150T,
136	10
143	10	S143F, S143P, S143Y,
161	11
142	11
162	11	V162M,
140	11	S140G, S140R, S140R, S140R,
135	11
148	11
163	12
138	12
217	13
213	13
132	13	I132L,
230	13
234	13	Q234H, Q234H,
141	13	V141M,
137	14	L137F, L137P,
144	14	T144A,
145	14
216	14	G216R,
147	14	Q147R,
164	14
226	14	A226V,
231	14	R231C, R231H, R231S,
133	15	V133I,
146	15	E146K, E146G, E146Q,
222	15